In utero estrogenic endocrine disruption alters the stroma to increase extracellular matrix density and mammary gland stiffness.

BACKGROUND: In utero endocrine disruption is linked to increased risk of breast cancer later in life. Despite numerous studies establishing this linkage, the long-term molecular changes that predispose mammary cells to carcinogenic transformation are unknown. Herein, we investigated how endocrine disrupting compounds (EDCs) drive changes within the stroma that can contribute to breast cancer susceptibility. METHODS: We utilized bisphenol A (BPA) as a model of estrogenic endocrine disruption to analyze the long-term consequences in the stroma. Deregulated genes were identified by RNA-seq transcriptional profiling of adult primary fibroblasts, isolated from female mice exposed to in utero BPA. Collagen staining, collagen imaging techniques, and permeability assays were used to characterize changes to the extracellular matrix. Finally, gland stiffness tests were performed on exposed and control mammary glands. RESULTS: We identified significant transcriptional deregulation of adult fibroblasts exposed to in utero BPA. Deregulated genes were associated with cancer pathways and specifically extracellular matrix composition. Multiple collagen genes were more highly expressed in the BPA-exposed fibroblasts resulting in increased collagen deposition in the adult mammary gland. This transcriptional reprogramming of BPA-exposed fibroblasts generates a less permeable extracellular matrix and a stiffer mammary gland. These phenotypes were only observed in adult 12-week-old, but not 4-week-old, mice. Additionally, diethylstilbestrol, known to increase breast cancer risk in humans, also increases gland stiffness similar to BPA, while bisphenol S does not. CONCLUSIONS: As breast stiffness, extracellular matrix density, and collagen deposition have been directly linked to breast cancer risk, these data mechanistically connect EDC exposures to molecular alterations associated with increased disease susceptibility. These alterations develop over time and thus contribute to cancer risk in adulthood.

Characterizing risk factors for hospitalization for psoriasis patients.

Psoriasis is a chronic autoimmune disease with a large economic impact. Inpatient care is a significant expense, and about one-third of patients admitted for psoriasis are readmitted. Reducing hospitalizations and readmissions is an important goal for improving outcomes for psoriasis patients. The objective of this study is to characterize patients who are hospitalized for psoriasis, and differentiate features for patients with a single hospitalization from those who were hospitalized multiple times during the study period. Hospitalized psoriasis patients were identified from an in-patient database at a single academic institution. Differences between psoriasis patients with one hospitalization and those with multiple hospitalizations were characterized, as were differences between patients who were hospitalized primarily for psoriasis and those who were admitted primarily for other reasons. Patients who were primarily hospitalized for psoriasis had fewer comorbidities, shorter hospitalizations, and a lower death rate than those hospitalized for other reasons. Patients with multiple hospitalizations had more comorbidities and worse outcomes than patients with a single hospitalization. Patients who are hospitalized primarily for psoriasis are more likely to be pustular, and tend to have fewer comorbidities and better outcomes than patients with psoriasis who are hospitalized with psoriasis as a secondary diagnosis. One limitation of this study is the lack of data available to consistently quantify disease severity, such as percent of body surface area affected by psoriasis or Physician's Global Assessment score.

Varying Susceptibility of the Female Mammary Gland to In Utero Windows of BPA Exposure.

In utero exposure to the endocrine disrupting compound bisphenol A (BPA) is known to disrupt mammary gland development and increase tumor susceptibility in rodents. It is unclear whether different periods of in utero development might be more susceptible to BPA exposure. We exposed pregnant CD-1 mice to BPA at different times during gestation that correspond to specific milestones of in utero mammary gland development. The mammary glands of early-life and adult female mice, exposed in utero to BPA, were morphologically and molecularly (estrogen receptor-α and Ki67) evaluated for developmental abnormalities. We found that BPA treatment occurring before mammary bud invasion into the mesenchyme [embryonic day (E)12.5] incompletely resulted in the measured phenotypes of mammary gland defects. Exposing mice up to the point at which the epithelium extends into the precursor fat pad (E16.5) resulted in a nearly complete BPA phenotype and exposure during epithelial extension (E15.5 to E18.5) resulted in a partial phenotype. Furthermore, the relative differences in phenotypes between exposure windows highlight the substantial correlations between early-life molecular changes (estrogen receptor-α and Ki67) in the stroma and the epithelial elongation defects in mammary development. These data further implicate BPA action in the stroma as a critical mediator of epithelial phenotypes.